Substituted 1,3-diaryl-2-pyrid-2-yl-3-(pyrid-2-ylamino)propanol derivatives, process for their preparation, pharmaceuticals comprising these compounds and their use

ABSTRACT

Substituted 1,3-diaryl-2-pyridin-2-yl-3-(pyridin-2-ylamino)propanol derivatives of the formula (I), and salts thereof,                    
     in which the radicals have the meanings given in the specification, and physiologically tolerated salts thereof and processes for their preparation are described. The compounds are suitable, for example, as hypolipidemic agents.

RELATED APPLICATIONS

Under the provisions of Section 119 of 35 U.S.C., Applicants herebyclaim the benefit of the filing date of Federal Republic of GermanyPatent Application Number 19845406.6, filed Oct. 2, 1998, whichApplication is hereby incorporated by reference.

The present invention relates to substituted1,3-diaryl-2-pyridin-2-yl-3-(pyridin-2-ylamino)propanol derivatives andpharmaceutically tolerated salts and physiologically functionalderivatives thereof.

BACKGROUND OF THE INVENTION

Several classes of active compounds for treatment of adiposity anddisturbances in lipid metabolism have already been described, e.g.,

polymeric adsorbers, such as cholestyramine,

benzothiazepines (WO 93/16055),

bile acid dimers and conjugates (EP 0 489 423), and

4-amino-2-ureido-pyrimidine-5-carboxamides (EP 0 557 879).

SUMMARY OF THE INVENTION

The object of the present invention is to provide further compoundsdisplaying a therapeutically valuable hypolipidemic action.

The present invention therefore relates to1,3-diaryl-2-pyridin-2-yl-3-(pyridin-2-ylamino)propanol derivatives offormula (I) or salts thereof,

wherein:

Z is

—NH—(C₁-C₁₆-alkyl)-(C═O)—,

—(C═O)—(C₁-C₁₆-alkyl)-(C═O)—, or

—(C═O)-phenyl-(C═O)—;

A¹, A², A³, A⁴, each independently of one another is an amino acidradical, or an amino acid radical which is mono- or polysubstituted byamino acid-protective groups;

E is —SO₂—R⁴ or —CO—R⁴;

R¹ is phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl, furanyl,pyridyl, or pyrimidyl, wherein the rings are unsubstituted, orsubstituted up to 3 times by F, Cl, Br, —OH, —CF₃, —NO₂, —CN, —OCF₃,—(C₁-C₆)-alkyl, —O—(C₁-C₆)-alkyl, —S—(C₁-C₆)-alkyl, —SO—(C₁-C₆)-alkyl,—SO₂—(C₁-C₆)-alkyl, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —COOH,—COO—(C₁-C₆)-alkyl, —COO—(C₃-C₆)cycloalkyl, —CONH₂, —CONH—(C₁-C₆)-alkyl,—CON[(C₁-C₆)-alkyl]₂, —CONH—(C₃-C₆)-cycloalkyl, —NH₂,—NH—CO—(C₁-C₆)-alkyl, or —NH—CO-phenyl;

R² is H, —OH, —CH₂OH, or —OMe;

R³ is H, F, methyl, or —OMe;

R⁴ is —(C₁-C₁₆-alkyl), —(C₀-C₁₆-alkylene)-R⁵,—(C═O)—(C₀-C₁₆-alkylene)-R⁵, —(C═O)—(C₀-C₁₆-alkylene)-NH—R⁵,—(C₁-C₈-alkenylene)-R⁵, —(C₁-C₈-alkynyl), —(C₁-C₄-alkylene)-S(O)_(r)—R⁵,—(C₁-C₄-alkylene)-O—R⁵, or —(C₁-C₄-alkylene)-NH—R⁵;

R⁵ is —COO—R⁶, —(C═O)—R⁶, —(C₁-C₆-alkylene)-R⁷, —(C₁-C₆-alkenylene)-R⁷,—(C₁-C₇)-cycloalkyl, phenyl, naphthyl, thienyl, thiophenyl, furanyl,pyridyl, pyrimidyl, dihydropyrimidine-2,4-dion-6-yl, chromanyl,phthalimidoyl, or thiazolyl, wherein the rings are unsubstituted, orsubstituted up to 3 times by F, Cl, Br, —OH, —CF₃, —NO₂, —CN, —OCF₃,—(C₁-C₆)-alkyl, —O—(C₁-C₆)-alkyl, —S—(C₁-C₆)-alkyl, —SO—(C₁-C₆)-alkyl,—SO₂—(C₁-C₆)-alkyl, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —COOH,—COO—(C₁-C₆)-alkyl, —COO—(C₃-C₆)-cycloalkyl, —CONH₂,—CONH—(C₁-C₆)-alkyl, —CON[(C₁-C₆)-alkyl]₂, —CONH—(C₃-C₆)-cycloalkyl,—NH₂, —NH—CO—(C₁C₆)-alkyl, —NH—CO-phenyl, or pyridyl;

R⁶ is H or —(C₁-C₆)-alkyl;

R⁷ is H, —(C₁-C₇)-cycloalkyl, phenyl, naphthyl, thienyl, thiophenyl,furanyl, pyridyl, pyrimidyl, dihydropyrimidine-2,4-dion-6-yl, chromanyl,phthalimidoyl, or thiazolyl, wherein the rings are unsubstituted, orsubstituted up to 3 times by F, Cl, Br, —OH, —CF₃, —NO₂, —CN, —OCF₃,—(C₁C₆)-alkyl, —O—(C₁-C₆)-alkyl, —S—(C₁-C₆)-alkyl, —SO—(C₁-C₆)-alkyl,—SO₂—(C₁-C₆)-alkyl, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —COOH,—COO—(C₁-C₆)-alkyl, —COO—(C₃-C₆)-cycloalkyl, —CONH₂,—CONH—(C₁-C₆)-alkyl, —CON[(C₁-C₆)-alkyl]₂, —CONH—(C₃-C₆)-cycloalkyl,—NH₂, —NH—CO—(C₁-C₆)-alkyl, or —NH—CO-phenyl;

l, q, m, n, o, p each independently of one another is 0 or 1, where thesum of l+q+m+n+o+p is greater than or equal to 1; and

r is 0, 1, or 2;

with the proviso that in formula (I), when R¹ is unsubstituted phenyl,R² is H, R³ is H, and l, m, n, o, and p are all zero, then R⁴ is otherthan —CH₃ or —C(CH₃)₃.

Preferred compounds of formula (I) or salts thereof are those in whichone or more radical(s) has or have the following meaning:

Z is

—NH—(C₁-C₁₆-alkyl)-(C═O)—,

—(C═O)—(C₁-C₁₆-alkyl)-(C═O)—, or

—(C═O)-phenyl-(C═O)—;

A¹, A², A³, A⁴, each independently of one another is an amino acidradical, or an amino acid radical which is mono- or polysubstituted byamino acid-protective groups;

E is —SO₂—R⁴ or —CO—R⁴;

R¹ is phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl, furanyl,pyridyl, or pyrimidyl, wherein the rings are unsubstituted orsubstituted up to 3 times by F, Cl, Br, —OH, —CF₃, —NO₂, —CN, —OCF₃,—(C₁-C₆)-alkyl, —O—(C₁-C₆)-alkyl, —S—(C₁-C₆)-alkyl, —SO—(C₁-C₆)-alkyl,—SO₂—(C₁-C₆)-alkyl, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —COOH,—COO—(C₁-C₆)-alkyl, —COO—(C₃-C₆)-cycloalkyl, —CONH₂,—CONH—(C₁-C₆)-alkyl, —CON[(C₁-C₆)-alkyl]₂, —CONH—(C₃-C₆)-cycloalkyl,—NH₂, —NH—CO—(C₁-C₆)-alkyl, or —NH—CO-phenyl;

R² is H, —OH, —CH₂OH, or —OMe;

R³ is H, F, methyl, or —OMe;

R⁴ is —(C₁-C₁₆-alkyl), —(C₀-C₁₆-alkylene)-R⁵,—(C═O)—(C₀-C₁₆-alkylene)-R⁵, —(C═O)—(C₀-C₁₆alkylene)-NH—R⁵,—(C₁-C₈-alkenylene)-R⁵, —(C₁-C₈-alkynyl), —(C₁-C₄-alkylene)-S(O)_(r)R⁵,—(C₁-C₄-alkylene)-O—R⁵ or —(C₁-C₄-alkylene)-NH—R⁵;

R⁵ is —COO—R⁶, —(C═O)—R⁶, —(C₁-C₆-alkylene)-R⁷, —(C₁-C₆-alkenylene)-R⁷,—C₁-C₇)-cycloalkyl, phenyl, naphthyl, thienyl, thiophenyl, furanyl,pyridyl, pyrimidyl, dihydropyrimidine-2,4-dion-6-yl, chromanyl,phthalimidoyl, or thiazolyl, wherein the rings are unsubstituted orsubstituted up to 3 times by F, Cl, Br, —OH, —CF₃, —NO₂, —CN, —OCF₃,—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, —S—(C₁-C₆)-alkyl, —SO—(C₁-C₆)-alkyl,—SO₂—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —COOH,—COO—(C₁-C₆)-alkyl, —COO—(C₃-C₆)-cycloalkyl, —CONH₂,—CONH—(C₁-C₆)-alkyl, —CON[(C₁-C₆)alkyl]₂, —CONH—(C₃-C₆)-cycloalkyl,—NH₂, —NH—CO—(C₁-C₆)-alkyl, —NH—CO-phenyl, or pyridyl;

R⁶ is H or —(C₁-C₆)-alkyl;

R⁷ is H, —(C₁-C₇)-cycloalkyl, phenyl, naphthyl, thienyl, thiophenyl,furanyl, pyridyl, pyrimidyl, dihydropyrimidine-2,4-dion-6-yl, chromanyl,phthalimidoyl, or thiazolyl, wherein the rings are unsubstituted orsubstituted up to 3 times by F, Cl, Br, —OH, —CF₃, —NO₂, —CN, —OCF₃,—(C₁-C₆)-alkyl, —O—(C₁-C₆)-alkyl, —S—(C₁-C₆)-alkyl, —SO—(C₁-C₆)-alkyl,—SO₂—(C₁-C₆)-alkyl, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —COOH,—COO—(C₁-C₆)-alkyl, —COO—(C₃-C₆)-cycloalkyl, —CONH₂,—CONH—(C₁-C₆)-alkyl, —CON[(C₁-C₆)alkyl]₂, —CONH—(C₃-C₆)-cycloalkyl,—NH₂, —NH—CO—(C₁-C₆)-alkyl, or —NH—CO-phenyl;

l is 0 or 1;

m, n are 0;

o is 1;

p is 0 or 1;

q is 0 or 1; and

r is 0, 1, or 2.

Particularly preferred compounds of formula (I) or salts thereof arethose in which one or more radical(s) has or have the following meaning:

Z is

—NH—(C₁-C₁₂-alkyl)-(C═O)—,

—(C═O)—(C₁-C₁₂-alkyl)-(C═O)—, or

—(C═O)-phenyl-(C═O)—;

A¹, A², A₃, A⁴ each independently of one another is an amino acidradical, or an amino acid radical which is mono- or polysubstituted byamino acid-protective groups;

E is —SO₂—R⁴ or —CO—R⁴;

R¹ is phenyl, thiazolyl, or oxazolyl, wherein the rings areunsubstituted or substituted up to 3 times by —(C₁-C₆)-alkyl;

R² is H, —OH, —CH₂OH, or —OMe;

R³ is H, F, methyl, or —OMe;

R⁴ is —(C₁-C₁₆-alkyl), —(C₀-C₁₆-alkylene)-R⁵,—(C═O)—(C₀-C₁₆-alkylene)-R⁵, —(C═O)—(C₀-C₁₆-alkylene)-NH—R⁵,—(C₁-C₈-alkenylene)-R⁵, —(C₁-C₈-alkynyl), —(C₁-C₄-alkylene)-S(O)_(r)—R⁵,—(C₁-C₄-alkylene)-O—R⁵, or —(C₁-C₄-alkylene)-NH—R⁵;

R⁵ is —COO—R⁶, —(C═O)—R⁶, —(C₁-C₇)-cycloalkyl, phenyl, naphthyl,thienyl, thiophenyl, furanyl, pyridyl, pyrimidyl,dihydropyrimidine-2,4-dion-6-yl, chromanyl, phthalimidoyl, or thiazolyl,wherein the rings are unsubstituted or substituted up to twice by F, Cl,Br, —OH, —CF₃, —NO₂, —CN, —OCF₃, —(C₁-C₆)-alkyl, —O—(C₁-C₆)-alkyl,—COOH, —COO—(C₁-C₆)-alkyl, —CONH₂, —CONH—(C₁-C₆)-alkyl,—CON[(C₁-C₆)alkyl]₂, —CONH—(C₃-C₆)-cycloalkyl, —NH₂,—NH—CO—(C₁-C₆)-alkyl, —NH—CO-phenyl, or pyridyl;

R⁶ is H or —(C₁-C₆)-alkyl;

l, m, n is 0;

o is 1;

p is 0 or 1;

q is 0 or 1; and

r is 0, 1, or 2.

DETAILED DESCRIPTION OF THE INVENTION

The term alkyl is understood as meaning straight-chain or branchedhydrocarbon chains. The phrase “each independently of one another is”means each radical is individually selected without reference to theselection of the other radicals. Therefore, this phrase includessituations where the radicals are all identical to one another, wherethey are all different from one another, and where some radicals areidentical to one another and others are different.

The terms amino acid(s) or amino acid radical(s) mean the stereoisomericforms, i.e., D- or L-forms, of any of the following compounds:

alanine glycine proline cysteine histidine glutamine aspartic acidisoleucine arginine glutamic acid lysine serine phenylalanine leucinethreonine tryptophan methionine valine tyrosine asparagine 2-aminoadipicacid 2-aminoisobutyric acid 3-aminoadipic acid 3-aminoisobutyric acidbeta-alanine 2-aminopimelic acid 2-aminobutyric acid 2,4-diaminobutyricacid 4-aminobutyric acid desmosine piperidic acid 2,2-diaminopimelicacid 6-aminocaproic acid 2,3-diaminopropionic acid 2-aminoheptanoic acidN-ethylglycine 2-(2-thienyl)-glycine 3-(2-thienyl)-alanine penicillaminesarcosine N-ethylasparagine N-methylisoleucine hydroxylysine6-N-methyllysine allo-hydroxylysine N-methylvaline 3-hydroxyprolinenorvaline 4-hydroxyproline norleucine isodesmosine ornithineallo-isoleucine 3-(2-naphthyl)alanine azaglycine N-cyclohexylglycine2,4-diaminobutyric acid

Abbreviation of the amino acids is in accordance with customarynomenclature (cf. Schröder, Lübke, The Peptides, Volume I, New York1965, pages XXII-XXIII; Houben-Weyl, Methoden der Organischen Chemie(Methods of Organic Chemistry), Volume XV/1 and 2, Stuttgart 1974). Theamino acid pGlu represents pyroglutamyl, Nal represents3-(2-naphthyl)alanine, Azagly-NH₂ represents a compound of the formulaNH₂—NH —CONH₂ and D-Asp represents the D-form of aspartic acid. Peptidesare acid amides in their chemical nature and dissociate into amino acidson hydrolysis.

The present invention furthermore relates to processes for thepreparation of compounds of formula (I) which comprise the followingreaction equations (Equations 1 to 6).

The compounds of formula (I) and their salts according to the presentinvention are prepared starting from compounds of formulae VI or VII instages from the free amino group or by coupling of segments by thegeneral methods of peptide chemistry (Houben-Weyl Methoden derOrganischen Chemie, Volume 15/1,2). The peptide couplings can be carriedout, for example, with TOTU (for literature examples see: G. Breipohl,W. König EP 0460446; W. König, G. Breipohl, P. Pokomy, M. Birkner in E.Giralt and D. Andreu (Eds.) Peptides 1990, Escom, Leyden, 1991, 143-145)by the method of mixed anhydrides, via active esters, azides or by thecarbodiimide method, in particular with the addition of substances whichaccelerate the reaction and prevent racemization, such as1-hydroxybenzotriazole, N-hydroxysuccinimide,3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine, orN-hydroxy-5-norbornene-2,3-dicarboximide, and furthermore using activederivatives of 1-hydroxybenzotriazole or anhydrides of phosphoric,phosphonic and phosphinic acids, at a reaction temperature of between−10° C. and the boiling point of the solvent, preferably between −5° C.and 40° C.

Suitable solvents for this are dimethylformamide, dimethylacetamide,N-methylpyrrolidone or dimethyl sulfoxide. If the solubility of thecomponents allows, solvents such as methylene chloride, chloroform ortetrahydrofuran or mixtures of solvents can also be employed. Suitablemethods are described in Meinhofer-Gross, “The Peptides” Academic Press,Volume I, (1979), among others.

If necessary to prevent side reactions, or for the synthesis of specificpeptides, the functional groups in the amino acid side chain areadditionally protected by suitable protective groups (see, for example,T. W. Greene, “Protective Groups in Organic Synthesis”). Primaryexamples are Arg(BOC)₂, Arg(Tos), Arg(Mts), Arg(Mtr), Arg(PMV),Asp(OBzl), Asp(OBut), Cys(4-MeBzl), Cys(Acm), Cys(SBut), Glu(OBzl),Glu(OBut), His(Tos), His(Fmoc), His(Dnp), His(Trt), Lys(Cl-Z), Lys(Boc),Met(O), Ser(Bzl), Ser(But), Thr(Bzl), Thr(But), Trp(Mts), Trp(CHO),Tyr(Br-Z), Tyr(Bzl) or Tyr(But).

The benzyloxycarbonyl (Z) radical, which can be split off by catalytichydrogenation, the 2-(3,5-dimethyloxyphenyl)propyl(2)oxycarbonyl (Ddz)or trityl (Trt) radical, which can be split off by weak acids, and the9-fluorenyl-methyloxycarbonyl (Fmoc) radical, which can be split off bysecondary amines, are typical examples of useful amino-protectivegroups. The SH group of cysteine can be blocked by a number ofprotective groups. The trityl (Trt) radical and the S-tert-butyl (StBu)radical are generally used for this purpose. The trityl radical can besplit off by iodine oxidation with formation of the cysteine compounds,or by reducing acid cleavage to give the cysteine compounds (LiebigsAnn. Chem. 1979, 227-247).

On the other hand, the S-tert-butyl radical is best split offreductively with tributylphosphine (Aust. J. Chem. 19 (1966) 2355-2360).OH and COOH functions in the side chains are best protected by thetert-butyl (tBu) radical, which can be split off under acid conditions(see also: Meienhofer-Gross: “The Peptides”, Volume 3). The compounds offormulae VI and VII are prepared as follows:

Compounds of type IV are obtained by reacting o-, m- or p-substitutedimines of type II with a ketone III. The reaction can be carried out,for example, by mixing the two compounds in bulk, without a solvent, andsubsequently heating the mixture, or in a suitable solvent such asethanol, tetrahydrofuran (THF), toluene, diglyme or tetradecane, attemperatures of from 20° C. to 150° C.

The keto compounds of type IV are reduced with NaBH₄ or other suitablereducing agent in a suitable solvent, such as methanol, THF, orTHF/water, at temperatures between −30° C. and +40° C. to give hydroxycompounds of type V. Two isomer mixtures (racemates) are usuallyobtained as the main products in the reduction. The different racematescan be separated from one another by fractional crystallization or bysilica gel chromatography. The nitro group in compounds of type V can bereduced by known processes, such as, for example, catalytichydrogenation with Pd or Pd-on-charcoal and H₂ in methanol.

The racemic compounds of type VI thus obtained can be separated furtherinto their enantiomers. The racemate splitting of VI into enantiomers oftype VII can be carried out by chromatography over chiral columnmaterial or by processes which are known from the literature, usingoptically active auxiliary reagents (cf. J. Org. Chem. 44, 1979, 4891).

In Preparation of compounds of formula (I) according to the presentinvention starting from compounds of type VI or VII is shown below.

Process A

Compounds of formula VI or VII are reacted with derivatives ofaminoalkanecarboxylic acids. Peptide coupling processes are employedhere. The aminoalkanecarboxylic acids, such as β-alanine orω-aminoundecanoic acid, are protected with Fmoc groups, andcorresponding nitro- or azidocarboxylic acids can also be used. Afterthe protective group has been split off in a second step, orcorrespondingly after reduction of the azido or nitro group, compoundsof formula VIII are obtained.

Compounds of formulae VI, VII or VIII can be reacted withamino-protected, for example Fmoc-protected, amino acids by peptidecoupling processes, and the side chains can be protected with suitableorthogonal protective groups, or can be unprotected. After the couplingreaction, the protective group of the amino function is split off, inthe case of Fmoc, for example, with piperidine in DMF. The compounds oftype IX thereby obtained can be reacted in one to three further reactionsequences, i.e., amino acid coupling and splitting off of theamino-protective group, to give compounds of formula X.

The protective groups of the side chains of the amino acids A¹ to A⁴,which number up to four, cain be split off individually after eachreaction sequence or together after all the coupling reactions, or allor some of them can also remain on the compounds X according to thepresent invention.

Process B

The free amino functions of compounds of formulae VI, VII, VIII, IX or Xare reacted with carboxylic acids, also by customary amide formationmethods. Functional groups of the starting compounds susceptible to sidereactions must be present in protected form, and can be split off afterthe reaction with the carboxylic acid, if necessary. The compoundsaccording to the present invention of type XI are obtained therefrom.

Process C

Analogously to process B, the sulfonamide derivatives XII are obtainedfrom the compounds of the formulae VI to IX. Accordingly, the aminofunctions of the starting compounds can be reacted, for example, withsulfonic acid chlorides in the presence of an auxiliary base in asuitable solvent.

Process D

Compounds of type XIII can be obtained by reaction of dicarboxylic acidmonoalkyl esters with compounds of type VI or VII, X representing analkyl or a phenyl radical, in accordance with the claims. The reactionis carried out by customary peptide coupling processes. The alkyl esterfunction is then hydrolyzed to the carboxylic acid in order to obtaincompounds of the formula XIV. The compounds XIV can also be obtaineddirectly from the amines of type VI or VII by reaction with dicarboxylicacid anhydrides, for example, succinic anhydride, in the presence of abase. If the carboxylic acid function of the compounds XIV is reactedwith amino acid alkyl esters which a protective group may carry in theside chain, compounds of formula XV are obtained. The compounds offormula XVI are in turn prepared therefrom by hydrolysis of the alkylester function.

Processes A-D can also be modified such that the compounds according tothe reactions may be prepared by reactions on a solid phase. This isshown in process E as a general example.

Process E

The compound of formula V is coupled to a modified polystyrene resin.For this, the carboxyl group of Carboxy-Tentagel (Rapp, Tübingen) isreacted with the OH function of the compound VI by esterificationmethods, for example, DCC or DMAP. The nitro group of compound XVII thusobtained is converted into the amino function by suitable methods, forexample, SuCl₂ reduction processes. On derivative XVIII, which is bondedto the solid phase, the side chain(E)₇—(A⁴)_(p)—(A³)_(o)—(A²)_(n)—(A¹)_(m)—(Z)_(e) is built up to thedesired length analogously to the peptide coupling processes alreadydescribed. In the last step, the compounds of formula (I) according tothe present invention are split off from the solid phase by hydrolysisof the ester group under basic conditions.

The radicals described as protective groups of amino acid side chains inthe processes described can remain in the compounds according to thepresent invention or can be split off by known methods (see T. W.Greene, “Protective Groups in Organic Synthesis”).

The compounds of formula (I) thus obtained can optionally be convertedinto their pharmaceutically tolerated salts or physiologicallyfunctional derivatives.

Because of their higher solubility in water compared with the startingor base compounds, pharmaceutically tolerated salts are particularlysuitable for medical uses. These salts must have a pharmaceuticallytolerated anion or cation. Suitable pharmaceutically tolerated acidaddition salts of the compounds according to the present invention aresalts of inorganic acids, such as hydrochloric, hydrobromic, phosphoric,metaphosphoric, nitric, sulfonic and sulfuric acid, and of organicacids, such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic,fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic,malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric andtrifluoroacetic acid. For medical purposes, the chlorine salt isparticularly preferable. Suitable pharmaceutically tolerated basic saltsare ammonium salts, alkali metal salts (such as sodium and potassiumsalts) and alkaline earth metal salts (such as magnesium and calciumsalts).

Salts with an anion which is not pharmaceutically tolerated are alsoincluded in the scope of the present invention as beneficialintermediate products for the preparation or purification ofpharmaceutically tolerated salts and/or for use in non-therapeuticapplications, such as in vitro applications.

The term “physiologically functional derivative” used herein designatesany physiologically tolerated derivative of a compound according to thepresent invention, i.e., an ester, which, when administered to a mammal,specifically a human, is capable of forming (either directly orindirectly) such a compound or an active metabolite thereof.

Prodrugs of the compounds according to the present invention are anotheraspect of the present invention. Such prodrugs can be metabolized invivo to give a compound according to the invention. These prodrugs ofthe compounds of formula (I) are, for example esters, amides, aldehydesor alcohols obtainable from carboxy groups, or acyl derivatives like(C₁-C₆)-alkylcarbonyl, (C₁-C₆)-alkyloxycarbonyl, oraryl-(C₁-C₄)-alkyloxycarbonyl derivatives obtainable from acylatablegroups including amino groups, imino groups, guanidino groups andamidino groups. These prodrugs can be active themselves or inactive.

The compounds according to the present invention can also exist invarious polymorphous forms, for example, as amorphous and crystallinepolymorphous forms. All the polymorphous forms of the compoundsaccording to the present invention are included in the scope of thepresent invention and are a further aspect of the present invention.

All references to “compound(s) according to formula (I)” or “compound(s)of formula (I)” in the prestent invention relate to compound(s) offormula (I) as described above and their salts, solvates andphysiologically functional derivatives as described herein.

The amount of a compound according to formula (I) necessary forachieving the desired biological effect depends on a number of factors,for example, the specific compound or salt chosen, the intended use, themode of administration and the clinical condition of the patient.

In general, the daily dose is in the range from 0.3 mg to 100 mg,typically from 3 mg to 50 mg, per day per kilogram of bodyweight, forexample 3-10 mg/kg/day. An intravenous dose can be, for example, in therange from 0.3 mg to 1.0 mg/kg, which can suitably be administered as aninfusion of 10 ng to 100 ng per kilogram per minute. Suitable infusionsolutions for this purpose can comprise, for example, from 0.1 ng to 10mg, typically from 1 ng to 10 mg per milliliter. Individual doses cancomprise, for example, from 1 mg to 10 g of the active compound. Thus,ampoules for injections can contain, for example, from 1 mg to 100 mg,and individual dose formulations for oral administration, such as, forexample, tablets or capsules, can contain, for example, from 1.0 to 1000mg, typically from 10 to 600 mg. In the case of pharmaceuticallytolerated salts, the abovementioned weight data relate to the weight ofthe benzothiazepine ion derived from the salt. For prophylaxis ortreatment of the abovementioned conditions, the compounds according toformula (I) can be used directly, but they are preferably presenttogether with a tolerated excipient in the form of a pharmaceuticalcomposition. The excipient must of course be tolerated in the sense thatit is compatible with the other constituents of the composition and doesnot harm the health of the patient. The excipient can be a solid or aliquid or both and is preferably formulated with the compound as anindividual dose, for example as a tablet, which can comprise from 0.05to 95% by weight of the active compound. Further pharmaceutically activesubstances can also be present, including further compounds according toformula (I). The pharmaceutical compositions according to the presentinvention can be prepared by one of the known pharmaceutical methods,which substantially comprise mixing the constituents withpharmacologically tolerated excipients and/or auxiliaries.

Pharmaceutical compositions according to the present invention are thosewhich are suitable for oral, rectal, topical, peroral (for examplesublingual) and parenteral (for example subcutaneous, intramuscular,intradermal or intravenous) administration, although the most suitablemode of administration in each individual case depends on the nature andseverity of the condition to be treated, and on the nature of theparticular compound according to formula (I) used. Coated formulationsand coated sustained-release formulations are also included in the scopeof the present invention. Formulations which are resistant to acid andto gastric juice are preferred. Suitable coatings which are resistant togastric juice include cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropylmethyl-cellulose phthalate, and anionic polymersof methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration can be presentin separate units, such as, for example, capsules, cachets, suckingtablets or tablets, each of which comprises a certain amount of thecompound according to formula (I); as powders or granules; as a solutionor suspension in an aqueous or non-aqueous liquid; or as an oil-in-wateror water-in-oil emulsion. As already mentioned, these compositions canbe prepared by any suitable pharmaceutical method which comprises a stepin which the active compound and the excipient (which can consist of oneor more additional constituents) are brought into contact. Thecompositions are in general prepared by uniform and homogeneous mixingof the active compound with a liquid and/or finely divided solidexcipient, after which the product is shaped, if necessary. Thus, forexample, a tablet can be prepared by pressing or shaping a powder orgranules of the compound, optionally with one or more additionalconstituents. Pressed tablets can be prepared by tableting the compoundin a free-flowing form, such as, for example, a powder or granules,optionally mixed with a binder, lubricant, inert diluent and/or one (ormore) surface-active/dispersing agents, in a suitable machine. Shapedtablets can be prepared by shaping the pulverulent compound, which hasbeen moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration include: sucking tablets, which comprise a compoundaccording to formula (I) with a flavoring substance, usually sucrose,and gum arabic or tragacanth; and pastilles, which comprise the compoundin an inert base, such as gelatin and glycerol, or sucrose and gumarabic.

Suitable pharmaceutical compositions for parenteral administrationinclude sterile aqueous formulations of a compound according to formula(I), which are normally isotonic with the blood of the intendedrecipient. These formulations are generally administered intravenously,although the administration can also take place subcutaneously,intramuscularly or intradermally as an injection. These formulations aregenerally prepared by mixing the compound with water and rendering theresulting solution sterile and isotonic with blood. Injectablecompositions according to the present invention in general comprise 0.1to 5% by weight of the active compound.

Suitable pharmaceutical compositions for rectal administration arepreferably in the form of individual-dose suppositories. These can beprepared by mixing a compound according to formula (I) with one or moreconventional solid excipients, for example, cacao butter, andintroducing the mixture formed into a mold.

Suitable pharmaceutical compositions for topical use on the skin arepreferably in the form of an ointment, cream, lotion, paste, spray,aerosol or oil. Vaseline, lanolin, polyethylene glycols, alcohols andcombinations of two or more of these substances can be used asexcipients. The active compound is in general present in a concentrationof 0.1 to 15% by weight of the composition, for example, 0.5 to 2%.

Transdermal administration is also possible. Suitable pharmaceuticalcompositions for transdermal applications can be in the form ofindividual patches which are suitable for long-term close contact withthe epidermis of the patient. Such patches suitably comprise the activecompound in an optionally buffered aqueous solution, dissolved and/ordispersed in an adhesion promoter or dispersed in a polymer. A suitableactive compound concentration is about 1% to 35%, preferably about 3% to15%. As a particular possibility, the active compound can be released byelectroporation or iontophoresis, as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

The present invention furthermore relates both to isomer mixtures offormula (I) and to the pure enantiomers of formula (I).

The compounds of formula (I) and their pharmaceutically tolerated saltsand physiologically functional derivatives thereof are idealpharmaceuticals for treatment of disturbances in lipid metabolism, inparticular, hyperlipidemia. The compounds of formula (I) are alsosuitable for influencing the serum cholesterol level and for preventionand treatment of arteriosclerotic symptoms. The following findingsdemonstrate the pharmacological activity of the compounds according tothe present invention.

Biological testing of the compounds according to the present inventionwas carried out by determining the inhibition of [³H]-taurocholateuptake in brush border membrane vesicles of the ileum of rabbits. Theinhibition test was carried out as follows:

1. Preparation of Brush Border Membrane Vesicles from the Ileum ofRabbits

Brush border membrane vesicles from the intestinal cells of the smallintestine were prepared by the so-called Mg²⁺ precipitation method. MaleNew Zealand rabbits (2 to 2.5 kg body weight) were sacrificed byintravenous injection of 0.5 ml T61®, an aqueous solution of 2.5 mgtetracaine HCl, 100 m embutramide and 25 mg mebezonium iodide. The smallintestine was removed and rinsed with ice-cold physiological salinesolution. The terminal 7/10 of the small intestine (measured in theoral-rectal direction, i.e., the terminal ileum, which contains theactive Na⁺-dependent bile acid transportation system) was used forpreparation of the brush border membrane vesicles. The intestines werefrozen in plastic bags under nitrogen at −80° C. For preparation of themembrane vesicles, the frozen intestines were thawed at 30° C. in awater bath. The mucosa was scraped off and suspended in 60 ml ofice-cold 12 mM TRIS/HCl buffer (pH 7.1)/300 mM mannitol, 5 mM EGTA/10mg/l of phenylmethylsulfonyl fluoride/1 mg/l of trypsin inhibitor fromsoybeans (32 U/mg)/0.5 mg/l of trypsin inhibitor from bovine lung (193U/mg)/5 mg/l of bacitracin. After dilution to 300 ml with ice-colddistilled water, the mixture was homogenized with an Ultraturrax(18-rod, IKA Werk Staufen, Germany) for 3 minutes at 75% of the maximumoutput by cooling with ice. After addition of 3 ml of 1 M MgCl₂ solution(final concentration 10 mM), the mixture was allowed to stand forexactly 1 minute at 0° C. The cell membranes aggregate by addition ofMg²⁺ and precipitate, with the exception of the brush border membranes.After centrifugation at 3000×g (5000 rpm, SS-34 rotor) for 15 minutes,the precipitate was discarded land the supernatant, which contains thebrush border membranes, was centrifuged at 48000×g (20000 rpm, SS-34rotor) for 30 minutes. The supernatant was discarded, and theprecipitate was rehomogenized in 60 ml of 12 mM TRIS/HCl buffer (pH7.1)/60 mM mannitol, 5 mM EGTA with a Potter Elvejhem homogenizer(Braun, Melsungen, 900 rpm, 10 strokes). After addition of 0.1 ml of 1 MMgCl₂ solution and incubation for 15 minutes at 0° C., centrifugationwas again carried out at 3000×g for 15 minutes. The supernatant was thencentrifuged again at 48000×x g (20000 rpm, SS-34 rotor) for 30 minutes.The precipitate was taken up in 30 ml of 10 mM TRIS/HEPES buffer (pH7.4)/300 mM mannitol and resuspended homogeneously by 20 strokes in aPotter Elvejhem homogenizer at 1000 rpm. After centrifugation at 48000×g(20000 rpm, SS-34 rotor) for 30 minutes, the precipitate was taken up in0.5 to 2 ml of TRIS/HEPES buffer (pH 7.4)/280 mM mannitol (finalconcentration 20 mg/ml) and resuspended with the aid of a Tuberculinsyringe with a 27-gauge needle. The vesicles were either used fortransportation investigations directly after preparation or stored at−196° C. in 4 mg portions in liquid nitrogen.

2. Inhibition of the Na⁺-dependent [³H]taurocholate Uptake in BrushBorder Membrane Vesicles of the Ileum

The uptake of substrates in the brush border membrane vesicles describedabove was determined by means of the so-called membrane filtrationtechnique. 10 μl of the vesicle suspension (100 μg of protein) werepipetted as drops onto the wall of a polystyrene incubation tube (11×70mm) which contained the incubation medium with the corresponding ligands(90 μl). The incubation medium comprised 0.75 μl=0.75 μCi[³H(G)]-taurocholate (specific activity: 2.1 Ci/mmol)/0.5 μl of 10 mMtaurocholate/8.75 μl of sodium transportation buffer (10 mM TRIS/HEPES(pH 7.4)/100 mM mannitol/100 mM NaCl) (Na-T-P) or 8.75 μl of potassiumtransportation buffer (10 mM TRIS/HEPES (pH 7.4)/100 mM mannitol/100 mMKCl) (K-T-P) and 80 μl of the inhibitor solution in question, dissolvedin Na-T buffer or K-T-buffer, depending on the experiment. Theincubation medium was filtered through a polyvinylidenefluoride membranefilter (SYHV LO 4NS, 0.45 μm, 4 mm Ø, Millipore, Eschborn, Germany).Mixing the vesicles with the incubation medium started thetransportation measurement. The concentration of taurocholate in theincubation batch was 50 μM. After the desired incubation time (usually 1minute), the transportation was stopped by addition of 1 ml of ice-coldstopping solution (10 mM TRIS/HEPES (pH 7.4)/150 mM KCl). The mixtureformed was immediately filtered with suction under a vacuum of between25 and 35 mbar over a membrane filter of cellulose nitrate (ME 25, 0.45μm, 25 mm diameter, Schleicher & Schuell, Dassell, Germany). The filterwas rinsed with 5 ml of ice-cold stopping solution.

To measure the uptake of the radioactively labeled taurocholate, themembrane filter was dissolved with 4 ml of the scintillator Quickszint361 (Zinsser Analytik GmbH, Frankfurt, Germany) and the radioactivitywas measured by liquid scintillation measurement in a TriCarb 2500measuring apparatus (Canberra Packard GmbH, Frankfurt, Germany). Thevalues measured were obtained as dpm (decompositions per minute) aftercalibration of the apparatus with the aid of standard samples and aftercorrection for any chemiluminescence present.

The control values were each determined in Na-T-P and K-T-P. Thedifference between the uptake in Na-T-P and K-T-P gave the Na⁺-dependenttransportation content. The concentration of inhibitor at which theNa⁺-dependent transporation content was inhibited by 50% as compared tothe control is designated the IC₅₀ Na⁺.

The pharmacological data comprise a test series in which the interactionof the compounds according to the present invention with the intestinalbile acid transportation system in the terminal small intestine wasinvestigated. The results are summarized in Table 1.

Table 1 shows measurement values of the inhibition of the[³H]-taurocholate uptake in brush border membrane vesicles of the ileumof rabbits. The quotients of the IC_(50Na) values of the referencesubstance as taurochenodeoxycholate (TCDC) and of the particular testsubstance are stated.

TABLE 1 IC_(50Na)-TCDC (μmol) Compounds from Example 1 {overscore(IC_(50Na)-compound (μmol))} 2c 1.06 3 0.88 6 0.77 7 0.87 14 0.21 150.94 16 0.16 17 1.26 18 0.69 19 1.05 20 0.30 21 0.17 22 0.82 31 1.13 330.52 34 0.81 35 0.36 36 0.36 38 0.38 41 0.61 44 1.05 45 1.03 47 1.00 490.86 50 0.67 52 1.11 53 0.46 56 1.15 57 0.79 60 0.62 61 0.66 62 0.99 640.39 65 0.84 66 0.93 69 1.00 73 0.92 74 0.70 77 0.22 78 0.27 82 0.79 830.24 87 0.84 89 0.90 91 0.92 93 1.10 94 0.40 143 0.26 144 1.16 145 1.19146 0.87 148 0.36 149 0.34 132 0.82 117 0.78 120 0.76

The following examples serve to illustrate the present invention in moredetail, without limitation to the products and embodiments described inthe examples.

EXAMPLE 1A

366 ml of 15% strength n-butyllithium in n-hexane were added dropwise to50 g (0.54 mol) of picoline in 770 ml of tetrahydrofuran at −55° C. Themixture was warmed to room temperature and cooled again to −55° C. 77 gof N,N-dimethylbenzamide (0.52 mol) in 570 ml of tetrahydrofuran wereslowly added dropwise, and the mixture was then warmed to roomtemperature and stirred for a further hour. After addition of 550 ml of1N hydrochloric acid, the mixture was extracted three times with ethylacetate and the organic phases were dried with MgSO₄ and evaporated.Distillation of the residue gave 47.5 g (47%) of the product. Boilingpoint 134-136° C./0.28 mbar.

EXAMPLE 1b

20.0 g (0.13 mol) of σ-nitrobenzaldehyde, 12.5 g (0.13 mol) of2-aminopyridine and 0.3 g of p-toluenesulfonic acid were heated underreflux in 150 ml of toluene for 2.5 hours, using a water separator. Thesolution was cooled and the precipitate formed was filtered off withsuction and dried.

Yield: 18.1 g (60%) of product

Melting point: 93-95° C.

C₁₂H₉N₃O₂ (227) MS (FAB) 228 M+H⁺

EXAMPLE 1c

12.0 g (61 mmol) of the ketone from Example 1a and 15.0 g (66 mmol) ofthe imine from Example 1b were heated on a steam bath for 45 minutes.The reaction mixture was dissolved in ethanol, with heating. Aftercooling, the precipitate was filtered off with suction andrecrystallized from ethanol.

Yield: 11.8 g (46%) of product

C₂₅H₂₀N₄O₃ (424.2) MS (FAB) 425 M+H⁺

EXAMPLE 1d

8.0 g (18.8 mmol) of the keto compound from Example 1c were dissolved in300 ml of tetrahydrofuran/water 10:1, 4.67 g of sodium borohydride wereadded and the mixture was stirred at room temperature for 2 hours. Thesolution was then evaporated, 100 ml of 2N hydrochloric acid were addedto the residue and the mixture was heated on a steam bath untileverything had dissolved. After cooling, the mixture was rendered basicwith 4N NaOH solution and extracted twice with ethyl acetate. Theorganic phases were dried with MgSO₄ and evaporated. The residue waschromatographed over silica gel (heptane/ethyl acetate 1:1). Two racemiccompounds were obtained as the product.

1st fraction: 3.9 g (48%) of non-polar racemate (Example 1d/1)

C₂₅H₂₂N₄O₃ (426.2) MS (FAB) 427 M+H⁺

2nd fraction: 2.5 g (31%) of polar racemate (Example 1d/2)

C₂₅H₂₂N₄O₃ (426.2) MS (FAB) 427 M+H⁺

EXAMPLE 1e

2.5 g (5.86 mmol) of the non-polar racemate from Example 1d/1 weredissolved in 300 ml of methanol, about 20 mg of Pd/C 10% were added andhydrogenation was carried out at room temperature under an H₂atmosphere. The catalyst was filtered off and the solution wasevaporated. The residue was chromatographed over silica gel(n-heptane/ethyl acetate 7:13).

Yield: 1.9 g (82%) of product

C₂₅H₂₄N₄O (396.22) MS (FAB) 397 M+H⁺

EXAMPLE 1f

100 mg of the racemic compound from Example 1e was separated into theenantiomers by preparative HPLC. The separation was carried out over aCSP-Chiralpak column (Daicel,Düsseldorf) with n-hexane/ethanol 4:1. 40mg of the (−)-enantiomer (Example 1f/1) were obtained as the 1stfraction and 40 mg of the (+)-enantiomer (Example 1f/2) were obtained asthe 2nd fraction.

EXAMPLE 1g

4.0 g (10.1 mmol) of the amino compound from Example 1e (non-polarracemate), 4.85 g (10.3 mmol) of N-Fmoc-D-Lys(BOC)OH, 4.0 g (12.2 mmol)of TOTU and 2.7 ml of triethylamine were dissolved in 300 ml ofdimethylformamide and the mixture was stirred at room temperature for 2hours. The reaction mixture was poured onto water and extracted twicewith ethyl acetate. The organic phases were dried (MgSO₄) andevaporated. The residue was dissolved in 150 ml ofdimethylformamide/piperidine 2:1, for splitting off the Fmoc group, andthe solution was stirred at room temperature for 1 hour. It was pouredonto water and extracted three times with ethyl acetate. The organicphases were dried (MgSO₄) and evaporated. Chromatography over silica gel(methylene chloride/methanol 9:1,) gave 4.0 g (63.5%) of the product.

C₃₆H₄₄N₆O₄ (624.3) MS (FAB) 625 M+H⁺

EXAMPLE 1h

4.74 g (43%) of the product were obtained from 8.0 g of the compoundfrom Example 1g (12.8 mmol) and 6.4 g (13.7 mmol) of N-Fmoc-D-Lys(BOC)OHby the process described under Example 1g.

C₄₇H₆₄N₈O₇ (852.5) MS (FAB) 853.5 M+H⁺

EXAMPLE 2a

2.5 g (6.31 mmol) of the amino compound from Example 1e (non-polarracemate), 2.2 g (6.52 mmol) of Fmoc-L-proline, 2.5 g (7.62 mmol) ofTOTU and 1.7 ml of triethylamine were dissolved in 100 ml ofdimethylformamide and the solution was stirred at room temperature for 3hours. The reaction mixture was evaporated to half of its originalvolume, water was added and the mixture was extracted three times withethyl acetate. The organic phases were dried over MgSO₄ and evaporated.After chromatography over silica gel (ethyl acetate/n-heptane, 7:3),3.85 g (85%) of product were obtained.

This Fmoc-protected intermediate product (3.6 g) was dissolved in 110 mlof piperidine/DMF, 1:10 and the solution was stirred at room temperaturefor 1 hour. The mixture was evaporated and chromatographed over silicagel (methylene chloride/methanol 19:1, then 9:1).

Yield: 1.8 g (72.5%)

C₃₀H₃₁N₅O₂ (493.2) MS (FAB) 494 M+H⁺

EXAMPLE 2b

1.7 g (3.44 mmol) of the compound from Example 2a were stirred with 1.4g (3.61 mmol) of Fmoc-L-phenylalanine, 1.9 g (5.80 mmol) of TOTU and 1.0ml of triethylamine in 150 ml of DMF at room temperature for 4 hours.The reaction mixture was evaporated and the residue was chromatographedover silica gel (ethyl acetate/n-heptane 4:1). Two fractions wereobtained:

1st fraction 1.28 g (43%) of non-polar diastereomer (Example 2b/1)

C₅₄H₅₀N₆O₅ (862.4) MS (FAB) 863.4 M+H⁺

2nd fraction 0.82 g (28%) of polar diastereomer (Example 2b/1)

C₅₄H₅₀N₆O₅ (862.4) MS(FAB) 863.4M+H⁺

EXAMPLE 2c

0.8 g (0.93 mmol) of the compound from Example 2b/2 were dissolved in 33ml of DMF/piperidine 10:1 and the solution was stirred at roomtemperature for 1 hour. After evaporation, the residue waschromatographed over silica gel (methylene chloride/methanol 19:1, then9:1).

Yield: 0.35 g (59%).

C₃₉H₄₀N₆O₃ (640.3) MS (FAB) 641.3 M+H⁺

The examples of Table 2 were obtained analogously to Example 1g andExample 2a, starting from Example 1e and Example 1f.

TABLE 2

Amino acid Empirical formula Example radical A¹ (molecular weight) MS(FAB) 3 Gly C₂₇H₂₇N₅O₂ (453.5) 454.5 M + H 4 L-Tyr(t-But) C₃₈H₄₁N₅O₃(615.7) 616.7 M + H⁺ 5 L-Ser(t-But) C₃₂H₃₇N₅O₃ (539.6) 540.6 M + H⁺ 6L-Lys(BOC) C₃₆H₄₄N₆O₄ (624.7) 625.7 M + H⁺ 7 L-Tyr C₃₄H₃₃N₅O₃ (559.6)560.6 M + H⁺ 8 L-Ser C₂₈H₂₉N₅O₃ (483.6) 484.6 M + H⁺ 9 L-Lys C₃₁H₃₆N₆O₂(524.7) 525.7 M + H⁺ 10 L-Arg(BOC)₂ C₄₁H₅₂N₈O₆ (752.9) 753.9 M + H⁺ 11L-Ornithine(BOC) C₃₅H₄₂N₆O₄ (610.7) 611.7 M + H⁺ 12 2,4-DiaminobutyricC₃₄H₄₀N₆O₄ (596.7) 597.7 M + H⁺ acid (BOC)

The examples of Table 3 were obtained analogously to Examples 1h and 2c,starting from Examples 1e and 1f.

TABLE 3

Amino Ex- acid Amino acid Empirical formula ample radical A¹ radical A²(molecular weight) MS (FAB) 13 Gly Gly C₂₉H₃₀N₆O₃ 511.6 M + H⁺ (polar)(510.6) 14 L-Lys L-Lys(BOC) C₄₇H₆₄N₈O₇ 854.1 M + H⁺ (non- (BOC) (853.1)polar) 15 L-Lys L-Lys(BOC) C₄₇H₆₄N₈O₇ 854.1 M + H⁺ (polar) (BOC) (853.1)16 L-Lys L-Ser(BOC) C₄₃H₅₇N₇O₆ 761.0 M + H⁺ (non- (BOC) (760.0) polar)17 L-Lys L-Ser(BOC) C₄₃H₅₇N₇O₆ 761.0 M + H⁺ (polar) (BOC) (760.0) 18L-Lys L-Arg C₄₂H₅₆N₁₀O₅ 782.0 M + H⁺ (non- (BOC) (781.0) polar) 19 L-LysL-Arg C₄₂H₅₆N₁₀O₅ 782.0 M + H⁺ (polar) (BOC) (781.0) 20 L-Phe L-Ser(BOC)C₄₁H₄₆N₆O₄ 687.8 M + H⁺ (686.8) 21 L-Phe L-Phe C₄₃H₄₂N₆O₃ 691.8 M + H⁺(690.8) 22 L-Phe L-Lys(BOC) C₄₅H₅₃N₇O₅ 773.0 M + H⁺ (772.0)

The examples of Table 4 were obtained analogously to Example 1g andExample 2a, starting from Example 1e and Example 1f.

TABLE 4 Ex- am- Empirical Molecular ple Formula formula mass MS (FAB) 30

C₃₀H₂₈N₆O₄ 536.6 537.6 M + H⁺ 31

C₃₀H₂₈N₄O₂ 476.6 477.6 M + H⁺ 32

C₃₃H₃₆N₄O₂S₂ 584.8 585.8 M + H⁺ 33

C₃₃H₂₉ClN₄O₂ 549.1 550.1 M + H⁺ 34

C₃₁H₂₈N₄O₂S 520.7 521.7 M + H⁺ 35

C₃₆H₃₆N₄O₄ 588.7 589.7 M + H⁺ 36

C₃₅H₃₁ClN₄O₃ 591.1 592.1 M + H⁺ 37

C₃₄H₃₂N₄O₄S 592.7 593.7 M + H⁺ 38

C₃₄H₂₉F₃N₄O₂ 582.6 583.6 M + H⁺ 39

C₃₁H₃₂N₄O₄ 524.6 525.6 M + H⁺ 40

C₃₄H₃₈N₄O₂ 534.7 535.6 M + H⁺ 41

C₃₁H₂₈N₄O₂S 520.7 521.7 M + H⁺ 42

C₃₄H₂₉FN₄O₂ 544.6 545.6 M + H⁺ 43

C₃₃H₂₉N₅O₅ 575.6 576.6 M + H⁺ 44

C₃₃H₂₉FN₄O₃ 548.6 549.6 M + H⁺ 45

C₃₄H₃₂N₄O₃ 544.7 545.6 M + H⁺ 46

C₃₃H₂₉ClN₄O₂S 581.1 582.1 M + H⁺ 47

C₃₅H₂₉N₅O₄ 583.6 584.6 M + H⁺ 48

C₃₆H₃₄N₄O₄ 586.7 587.7 M + H⁺ 49

C₃₃H₃₇N₅O₄ 567.7 568.7 M + H⁺ 50

C₂₉H₃₀N₄O₃ 482.6 483.6 M + H⁺ 51

C₃₄H₃₀N₄O₃ 542.6 543.6 M + H⁺ 52

C₃₅H₃₂N₄O₄ 572.7 573.7 M + H⁺ 53

C₃₂H₂₈N₄O₂S 532.7 533.7 M + H⁺ 54

C₃₈H₃₂N₄O₂ 576.7 577.7 M + H⁺ 55

C₃₆H₃₂N₄O₄ 584.7 585.7 M + H⁺ 56

C₃₁H₂₈N₆O₂S 548.7 549.7 M + H⁺ 57

C₃₁H₃₀N₄O₄ 522.6 523.6 M + H⁺ 58

C₃₁H₃₀N₄O₂ 490.6 491.6 M + H⁺ 59

C₃₄H₃₂N₄O₄ 560.7 561.7 M + H⁺ 60

C₃₃H₃₄N₄O₂ 518.7 519.7 M + H⁺ 61

C₃₂H₃₀N₆O₂S 562.7 563.7 M + H⁺ 62

C₃₀H₂₇N₅O₂ 489.6 490.6 M + H⁺ 63

C₃₄H₃₀C₁₂N₄O₂S 629.6 530.6 M + H⁺ 64

C₃₅H₃₃N₅O₄ 587.7 588.7 M + H⁺ 65

C₃₁H₂₇N₅O₅S 581.7 582.6 M + H⁺ 66

C₃₅H₃₆N₄O₃S 592.8 593.8 M + H⁺ 67

C₃₂H₂₇F₃N₄O₄S 620.6 521.6 M + H⁺ 68

C₃₉H₃₇N₇O₃S 683.8 584.8 M + H⁺ 69

C₃₅H₃₈N₄O₄S 610.8 611.6 M + H⁺ 70

C₃₄H₂₉N₅O₃S 587.7 588.7 M + H⁺ 71

C₃₃H₃₁ClN₄O₃S 599.2 600.2 M + H⁺ 72

C₃₄H₃₄N₄O₃S 578.7 579.7 M + H⁺ 73

C₃₁H₂₇FN₄O₃S 554.6 555.6 M + H⁺ 74

C₃₁H₂₆C₁₂N₄O₄S 621.5 522.5 M + H⁺ 75

C₃₁H₂₆N₆O₇S 626.6 627.6 M + H⁺ 76

C₃₁H₂₆C₁₂N₄O₃S 605.5 606.5 M + H⁺ 77

C₂₈H₃₀N₄O₃S 502.6 503.6 M + H⁺ 78

C₃₃H₂₆F₆N₄O₃S 672.6 573.6 M + H⁺ 79

C₃₂H₂₉BrN₄O₄S 645.6 646.6 M + H⁺ 80

C₄₁H₅₆N₄O₃S 685.0 686.0 M + H⁺ 81

C₂₉H₂₅BrN₄O₃S₂ 621.6 622.6 M + H⁺ 82

C₂₉H₂₅ClN₄O₃S₂ 577.1 578.1 M + H⁺ 83

C₃₉H₄₂N₄O₄S 662.9 663.9 M + H⁺ 84

C₃₅H₃₀N₄O₅S₃ 682.8 683.8 M + H⁺ 85

C₃₃H₃₀N₄O₅S 594.7 595.7 M + H⁺ 86

C₃₃H₄₀N₄O₃S 572.8 573.8 M + H⁺ 87

C₃₅H₃₆N₄O₄S 608.8 609.8 M + H⁺ 88

C₃₅H₃₀N₄O₃S 586.7 587.7 M + H⁺ 89

C₃₇H₃₅N₅O₃S 629.8 630.8 M + H⁺ 90

C₃₂H₂₆F₃N₅O₅S 649.6 650.6 M + H⁺ 91

C₃₂H₂₈N₄O₅S 580.7 581.7 M + H⁺ 92

C₃₆H₃₈N₄O₃S 606.8 607.8 M + H⁺ 93

C₃₁H₃₀N₆O₄S₂ 614.7 615.7 M + H⁺ 94

C₃₂H₃₀N₄O₅S₂ 614.7 615.7 M + H⁺

EXAMPLE 95

1.6 g of the amine of formula VI or VIII and 0.98 g of12-nitrododecanoic acid were dissolved in 30 ml of dimethylformamide.1.6 g ofO-((ethoxycarbonyl)cyanomethyleneamino)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TOTU), 0.6 g of ethyl (hydroxyimino)-cyanoacetate and1.6 ml of N-ethylmorpholine were added and the mixture was stirred atroom temperature for approximately 2 hours. When the reaction had ended(as indicated by thin layer chromatography), the reaction mixture wasextracted by stirring with 500 ml of water and 200 ml of methylenechloride and the organic phase was separated off, dried and concentratedin vacuo. After column chromatography (CC, SiO₂, ethylacetate/n-heptane=2:1), the amide was obtained as a viscous oil.Empirical formula:

C₃₇H₄₅N₅O₄; (623.4); MS(FAB): 624.4 M+H⁺

EXAMPLE 96

2.2 g of the amide were dissolved in 200 ml of ethanol and, afteraddition of a catalytic amount of Raney nickel (aqueous suspension),hydrogenation was carried out in a duck-shaped shaking vessel undernormal pressure at room temperature. The mixture was filtered off withsuction over a clarifying layer and concentrated to give, after CC(SiO₂, methylene chloride/methanol/ammonia=90:10:1) Example 96.Empirical formula: C₃₇H₄₇N₅O₂ (593.8) MS(FAB): 595 M+H⁺

EXAMPLE 97

1.2 g of Example 96, 390 mg of China acid and 330 mg ofN-hydroxy-benzotriazole were dissolved in 100 ml of tetrahydrofuran, and500 mg of dicyclohexylcarbodiimide were added. The mixture was stirredat room temperature for 17 hours, filtered and concentrated. The residuewas taken up in about 500 ml of ethyl acetate, extracted by shakingsuccessively with NaHCO₃ solution, 2N citric acid, NaHCO₃ solution andwater, and then dried and concentrated. After column filtration (ethylacetate/methanol =9:1), Example 97 was obtained, melting point 95° C.Empirical formula: C₄₄H₄₇N₅O₇ (768),

MS(FAB): 768.4 M+H⁺

EXAMPLE 98

593 mg of Example 96 and 265 mg of the carboxyl acid shown above weredissolved in 20 ml of DMF. 600′mg of TOTU, 300 mg of ethylhydroxy-imino-cyanoacetate and 1 ml of N-ethylmorpholine were added andthe mixture was stirred at room temperature for about 2 hours. When thereaction had ended (as indicated by thin layer chromatography), ethylacetate was added and the mixture was washed in each case twice withwater and NaHCO₃ solution, the organic phase was concentrated and theresidue was purified by column chromatography (SiO₂, ethylacetate/methanol=9:1). The amide Example 4 of melting point 105° C. wasobtained. Empirical formula: C₅₂H₅₆N₈O₃ (840.5); MS: 842 (M+H⁺)

The following substances were prepared analogously to Example 98 fromthe amine of Example 96 and the corresponding carboxylic acid:

TABLE 5 Empirical formula Example R⁴—COOH (mass number) MS (FAB) 99

C₄₀H₄₈N₆O₃ 660.4 661.5 (M + H⁺) 100

C₄₃H₅₇N₇O₄ 735.5 737 (M + H⁺) 101

C₄₂H₅₅N₅O₅ 709.4 711 (M + H⁺) 102

C₃₉H₄₇F₂N₅O₃ 671.4 673 (M + H⁺) 103

C₄₆H₅₃N₅O₅ 755.4 757 (M + H⁺) 104

C₄₃H₅₁N₇O₃ 713.4 715 (M + H⁺) 105

C₄₄H₅₃N₇O₃ 727.4 729 (M + H⁺) 106

C₄₂H₅₁N₅O₅ 705.4 707 (M + H⁺) 107

C₄₃H₅₆N₈O₄ 748.4 750 (M + H⁺) 108

C₄₅H₅₂N₆O₄ 740.4 741 (M + H⁺) 109

C₄₃H₅₅N₇O₅ 749.4 751 (M + H⁺) 110

C₄₀H₅₁N₅O₅S 713.4 715 (M + H⁺) 111

C₄₇H₅₆N₁₀O₆ 856.4 858 (M + H⁺) 112

C₄₂H₅₀N₈O₄S 762.4 764 (M + H⁺) 113

C₄₃H₅₃N₅O₅ 719.4 721 (M + H⁺) 114

C₄₂H₅₁N₇O₅ 733.4 735 (M + H⁺) 115

C₄₃H₅₃N₇O₄S 763.4 765 (M + H⁺) 116

C₄₈H₅₇N₇O₄ 795.5 797 (M + H⁺) 117

C₄₃H₅₁N₇O₃ 713.4 715 (M + H⁺) 118

C₄₆H₅₅N₉O₅ 813.4 815 (M + H⁺) 119

C₄₂H₅₁N₇O₃ 701.4 703 (M + H⁺) 120

C₄₈H₅₇N₅O₆ 799.4 801 (M + H⁺) 121

C₄₃H₅₆N₆O₄ 720.4 722 (M + H⁺) 122

C₄₂H₅₀N₆O₄S₂ 766.3 768 (M + H⁺) 123

C₄₁H₅₂N₆O₄ 692.4 694 (M + H⁺) 124

C₄₁H₅₀N₆O₄ 690.4 692 (M + H⁺) 125

C₄₆H₅₃N₅O₄ 739.4 741 (M + H⁺)

The examples of Tables 6 and 7 were obtained analogously to Process A,Equation 2 (see page 13).

TABLE 6

Empirical formula Amino acid (molecular Example R¹ radical A¹ weight) MS133 3,5- D-Lys(Boc) C₃₅H₄₅N₇O₅ 644.4 (FAB), Dimethyl- (643.8) M + H⁺isoxazol-4-yl 134 2,4- D-Lys(Boc) C₃₅H₄₅N₇O₄S 660.4 (ESI), Dimethyl-(659.9) M + H⁺ thiazol-5-yl 135 2,5- D-Lys(Boc) C₃₅H₄₅N₇O₅ 644.4 (FAB),Dimethyl- (643.8) M + H⁺ oxazol-4-yl

TABLE 7

Amino Ex- acid Amino acid Empirical formula ample R¹ radical A¹ radicalA² (molecular weight) MS (FAB) 143 3,5-Dimethyl- L-Proline L-Phenyl-C₃₈H₄₁N₇O₄ 660.3 (ESI), (highly isoxazolyl-4-yl alanine (659.8) M + H⁺non- polar) 144 3,5-Dimethyl- D-Lys(Boc) D-Lys(Boc) C₄₆H₆₅N₉O₈ 772.4(FAB), (highly isoxazolyl-4-yl (872.1) M + H⁺ non- polar) 1452,5-Dimethyl- D-Lys(Boc) D-Lys(Boc) C₄₆H₆₅N₉O₈ 772.5 (FAB), (highlyoxazol-4-yl (872.1) M + H⁺ non- polar) 146 5-Methyl- D-Lys(Boc)D-Lys(Boc) C₄₅H₆₃N₉O₈ 858.5 (FAB), (highly isoxazol-3-yl (858.1) M + H⁺non- polar 147 2,4-Dimethyl- D-Lys(Boc) D-Lys(Boc) C₄₆H₆₅N₉O₇S 888.6(ESI) (highly thiazol-5-yl (888.2) M + H⁺ non- polar) 148 2,4-Dimethyl-D-Lys(Boc) D-Lys(Boc) C₄₆H₆₅N₉O₇S 888.4 (FAB) non- thiazol-5-yl (888.2)M + H⁺ polar 149 2,4-Dimethyl- D-Lys(Boc) D-Lys(Boc) C₄₆H₆₅N₉O₇S 888.6(ESI) (moder- thiazol-5-yl (888.2) M + H⁺ ately polar) 150 2,4-Dimethyl-D-Lys(Boc) D-Lys(Boc) C₄₆H₆₅N₉O₇S 888.4 (FAB) S983499 thiazol-5-yl(888.2) M + H⁺ (polar) 151 2,4-Dimethyl- D-Lys(Boc) L-Phenyl-C₄₄H₅₄N₈O₅S 807.5 (ESI) (highly thiazol-5-yl alanine (807.0) M + H⁺ non-polar) 32 2,4-Dimethyl- L-Proline L-Phenyl- C₃₈H₄₁N₇O₃S 676.4 (FAB)(highly thiazol-5-yl alanine (675.9) M + H⁺ non- polar)

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects as illustrative onlyand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

We claim:
 1. A compound of the formula (I), or a salt thereof,

in which Z is —NH—(C₁-C₁₆-alkyl)-(C═O)—; —(C═O)—(C₁-C₁₆-alkyl)-(C═O)—;or —(C═O)-phenyl-(C═O)—; A¹, A², A³, A⁴, each independently of oneanother is the D- or L-form of alanine, glycine, proline, cysteine,histidine, glutamine, aspartic acid, isoleucine, arginine, glutamicacid, lysine, serine, phenylalanine, leucine, threonine, tryptophan,methionine, valine, tyrosine, asparagine, 2-aminoadipic acid,2-aminoisobutyric acid, 3-aminoadipic acid, 3-aminoisobutyric acid,beta-alanine, 2-aminopimelic acid, 2-aminobutyric acid,2,4-diaminobutyric acid, 4-aminobutyric acid, desmosine, piperidic acid,2,2-diaminopimelic acid, 6-aminocaproic acid, 2,3-diaminopropionic acid,2-aminoheptanoic acid, N-ethylglycine, 2-(2-thienyl)-glycine,3-(2-thienyl)-alanine, penicillamine, sarcosine, N-ethylasparagine,N-methylisoleucine, hydroxylysine, 6-N-methyllysine, allo-hydroxylysine,N-methylvaline, 3-hydroxyproline, norvaline, 4-hydroxyproline,norleucine, isodesmosine, ornithine, allo-isoleucine,3-(2-naphthyl)alanine, azaglycine, N-cyclohexylglycine, or2,4-diaminobutyric acid, E is —SO₂—R⁴, —CO—R⁴; R is phenyl, thiazolyl,oxazolyl, thienyl, thiophenyl, furanyl, pyridyl, or pyrimidyl, whereinthe rings are unsubstituted, or are substituted up to 3 times by F, Cl,Br, OH, CF₃, NO₂, CN, OCF₃, —(C₁-C₆)-alkyl, —O—(C₁-C₆)-alkyl,—S—(C₁-C₆)-alkyl, —SO—(C₁-C₆)-alkyl, —SO₂—(C₁-C₆)-alkyl, —(C₁-C₆)-alkyl,—(C₃-C₆)-cycloalkyl, —COOH, —COO(C₁-C₆)alkyl, —COO(C₃-C₆)cycloalkyl,—CONH₂, —CONH(C₁-C₆)alkyl, —CON[(C₁-C₆)alkyl]₂, —CONH(C₃-C₆)cycloalkyl,—NH₂, —NH—CO—(C₁-C₆)-alkyl, or —NH—CO-phenyl; R² is H, —OH, —CH₂OH, or—OMe; R³ is H, F, methyl, or —OMe; R⁴ is —(C₁-C₁₆-alkyl),—(C₀-C₁₆-alkylene)-R⁵, —(C═O)—(C₀-C₁₆-alkylene)-R⁵,—(C═O)—(C₀-C₁₆-alkylene)-NH—R⁵, —(C₁-C₈-alkenylene)-R⁵,—(C₁-C₈-alkynyl), —(C₁-C₄-alkylene)-S(O)_(r)—R⁵, —(C₁-C₄-alkylene)-O—R⁵,or —(C₁-C₄-alkylene)-NH—R⁵; R⁵ is —COO—R⁶, —(C═O)—R⁶,—(C₁-C₆-alkylene)-R⁷, —(C₁-C₆-alkenylene)-R⁷, —(C₁-C₇)-cycloalkyl,phenyl, naphthyl, thienyl, thiophenyl, furanyl, pyridyl, pyrimidyl,dihydropyrimidine-2,4-dion-6-yl, chromanyl, phthalimidoyl, or thiazolyl,wherein the rings are unsubstituted, or are substituted up to 3 times byF, Cl, Br, —OH, —CF₃, —NO₂, —CN, —OCF₃, —(C₁-C₆)-alkyl,—O—(C₁-C₆)-alkyl, —S—(C₁-C₆)-alkyl, —SO—(C₁-C₆)-alkyl,—SO₂—(C₁-C₆)-alkyl, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —COOH,—COO(C₁-C₆)alkyl, —COO(C₃-C₆)cycloalkyl, —CONH₂, —CONH(C₁-C₆)alkyl,—CON[(C₁-C₆)alkyl]₂, —CONH(C₃-C₆)cycloalkyl, —NH₂, —NH—CO—(C₁-C₆)-alkyl,—NH—CO-phenyl, or pyridyl; R⁶ is H or —(C₁-C₆)alkyl; R⁷ is H,—(C₁-C₇)-cycloalkyl, phenyl, naphthyl, thienyl, thiophenyl, furanyl,pyridyl, pyrimidyl, dihydropyrimidine-2,4-dion-6-yl, chromanyl,phthalimidoyl, or thiazolyl, wherein the rings are unsubstituted, or aresubstituted up to 3 times by F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,—(C₁-C₆)-alkyl, —O—(C₁-C₆)-alkyl, —S—(C₁-C₆)-alkyl, —SO—(C₁-C₆)-alkyl,—SO₂—(C₁-C₆)-alkyl, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —COOH,—COO(C₁-C₆)alkyl, —COO(C₃-C₆)cycloalkyl, —CONH₂, —CONH(C₁-C₆)alkyl,—CON[(C₁-C₆)alkyl]₂, —CONH(C₃-C₆)cycloalkyl, —NH₂, —NH—CO—(C₁-C₆)-alkyl,or —NH—CO-phenyl; l, q, m, n, o, p each independently of one another is0 or 1, where l+q+m+n+o+p is greater than or equal to 1; r is 0, 1, or2; with the proviso that in formula (I), when R¹ is unsubstitutedphenyl, R² is H, R³ is H, and l, m, n, o, and p are all zero, then R⁴ isother than —CH₃ or —C(CH₃)₃.
 2. A compound of the formula (I) or saltthereof as claimed in claim 1, wherein Z is —NH—(C₁-C₁₆-alkyl)-(C═O)—,—(C═O)—(C₁-C₁₆-alkyl)-(C═O)—, or —(C═O)-phenyl-(C═O)—; A¹, A², A³, A⁴each independently of one another is the D- or L-form of alanine,glycine, proline, cysteine, histidine, glutamine, aspartic acid,isoleucine, arginine, glutamic acid, lysine, serine, phenylalanine,leucine, threonine, tryptophan, methionine, valine, tyrosine,asparagine, 2-aminoadipic acid, 2-aminoisobutyric acid, 3-aminoadipicacid, 3-aminoisobutyric acid, beta-alanine, 2-aminopimelic acid,2-aminobutyric acid, 2,4-diaminobutyric acid, 4-aminobutyric acid,desmosine, piperidic acid, 2,2-diaminopimelic acid, 6-aminocaproic acid,2,3-diaminopropionic acid, 2-aminoheptanoic acid, N-ethylglycine,2-(2-thienyl)-glycine, 3-(2-thienyl)-alanine, penicillamine, sarcosine,N-ethylasparagine, N-methylisoleucine, hydroxylysine, 6-N-methyllysine,allo-hydroxylysine, N-methylvaline, 3-hydroxyproline, norvaline,4-hydroxyproline, norleucine, isodesmosine, ornithine, allo-isoleucine,3-(2-naphthyl)alanine, azaglycine, N-cyclohexylglycine, or2,4-diaminobutyric acid, E is —SO₂—R⁴, or —CO—R⁴; R¹ is phenyl,thiazolyl, oxazolyl, thienyl, thiophenyl, furanyl, pyridyl, orpyrimidyl, wherein the rings are unsubtituted, or are substituted up to3 times by F, Cl, Br, —OH, —CF₃, —NO₂, —CN, —OCF₃, —(C₁-C₆)-alkyl,—O—(C₁-C₆)-alkyl, —S—(C₁-C₆)-alkyl, —SO—(C₁-C₆)-alkyl,—SO₂—(C₁-C₆)-alkyl, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —COOH,—COO(C₁-C₆)alkyl, —COO(C₃-C₆)cycloalkyl, —CONH₂, —CONH(C₁-C₆)alkyl,—CON[(C₁-C₆)alkyl]₂, —CONH(C₃-C₆)cycloalkyl, —NH₂, —NH—CO—(C₁-C₆)-alkyl,or —NH—CO-phenyl; R² is H, —OH, —CH₂OH, or —OMe; R³ is H, F, methyl, or—OMe; R⁴ is —(C₁-C₁₆-alkyl), —(C₀-C₁₆-alkylene)-R⁵,—(C═O)—(C₀-C₁₆-alkylene)-R⁵, —(C═O)—(C₀-C₁₆-alkylene)-NH—R⁵,—(C₁-C₈-alkenylene)-R⁵, —(C₁-C₈-alkynyl), —(C₁-C₄-alkylene)-S(O)_(r)—R⁵,—(C₁-C₄-alkylene)-O—R⁵, or —(C₁-C₄-alkylene)-NH—R⁵; R⁵ is —COO—R⁶,—(C═O)—R⁶, —(C₁-C₆-alkylene)-R⁷, —(C₁-C₆-alkenylene)-R⁷,—(C₁-C₇)-cycloalkyl, phenyl, naphthyl, thienyl, thiophenyl, furanyl,pyridyl, pyrimidyl, dihydropyrimidine-2,4-dion-6-yl, chromanyl,phthalimidoyl, or thiazolyl, wherein the rings are unsubstituted, or aresubstituted up to 3 times by F, Cl, Br, —OH, —CF₃, —NO₂, —CN, —OCF₃,—(C₁-C₆)-alkyl, —O—(C₁-C₆)-alkyl, —S—(C₁-C₆)-alkyl, —SO—(C₁-C₆)-alkyl,—SO₂—(C₁-C₆)-alkyl, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —COOH,—COO(C₁-C₆)alkyl, —COO(C₃-C₆)cycloalkyl, —CONH₂, —CONH(C₁-C₆)alkyl,—CON[(C₁-C₆)alkyl]₂, —CONH(C₃-C₆)cycloalkyl, —NH₂, —NH—CO—(C₁-C₆)-alkyl,—NH—CO-phenyl, or pyridyl; R⁶ is H, or —(C₁-C₆)alkyl; R⁷ is H,—(C₁-C₇)-cycloalkyl, phenyl, naphthyl, thienyl, thiophenyl, furanyl,pyridyl, pyrimidyl, dihydropyrimidine-2,4-dion-6-yl, chromanyl,phthalimidoyl, or thiazolyl, wherein the rings are unsubstituted, or aresubstituted up to 3 times by F, Cl, Br, —OH, —CF₃, —NO₂, —CN, —OCF₃,—(C₁-C₆)-alkyl, —O—(C₁-C₆)-alkyl, —S—(C₁-C₆)-alkyl, —SO—(C₁-C₆)-alkyl,—SO₂—(C₁-C₆)-alkyl, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —COOH,—COO(C₁-C₆)alkyl, —COO(C₃-C₆)cycloalkyl, —CONH₂, —CONH(C₁-C₆)alkyl,—CON[(C₁-C₆)alkyl]₂, —CONH(C₃-C₆)cycloalkyl, —NH₂, —NH—CO—(C₁-C₆)-alkyl,or —NH—CO-phenyl; l is 0 or 1; m, n are 0; o is 1; p is 0 or 1; q is 0or 1; and r is 0, 1, or
 2. 3. A compound of formula (I), or a saltthereof, as claimed in claim 1, wherein: Z is —NH—(C₁-C₁₂-alkyl)-(C═O)—,—(C═O)—(C₁-C₁₂-alkyl)-(C═O)—, or —(C═O)-phenyl-(C═O)—; A¹, A², A³, A⁴each independently of one another is the D- or L-form of alanine,glycine, proline, cysteine, histidine, glutamine, aspartic acid,isoleucine, arginine, glutamic acid, lysine, serine, phenylalanine,leucine, threonine, tryptophan, methionine, valine, tyrosine,asparagine, 2-aminoadipic acid, 2-aminoisobutyric acid, 3-aminoadipicacid, 3-aminoisobutyric acid, beta-alanine, 2-aminopimelic acid,2-aminobutyric acid, 2,4-diaminobutyric acid, 4-aminobutyric acid,desmosine, piperidic acid, 2,2-diaminopimelic acid, 6-aminocaproic acid,2,3-diaminopropionic acid, 2-aminoheptanoic acid, N-ethylglycine,2-(2-thienyl)-glycine, 3-(2-thienyl)-alanine, penicillamine, sarcosine,N-ethylasparagine, N-methylisoleucine, hydroxylysine, 6-N-methyllysine,allo-hydroxylysine, N-methylvaline, 3-hydroxyproline, norvaline,4-hydroxyproline, norleucine, isodesmosine, ornithine, allo-isoleucine,3-(2-naphthyl)alanine, azaglycine, N-cyclohexylglycine, or2,4-diaminobutyric acid, E is —SO₂—R⁴, —CO—R⁴; R¹ is phenyl, thiazolyl,or oxazolyl, wherein the rings are unsubstituted, or are substituted upto 3 times by —(C₁-C₆)-alkyl; R² is H, OH, CH₂OH, or —OMe; R³ is H, F,methyl, or —OMe; R⁴ is —(C₁-C₁₆-alkyl), —(C₀-C₁₆-alkylene)-R⁵,—(C═O)—(C₀-C₁₆-alkylene)-R⁵, —(C═O)—(C₀-C₁₆-alkylene)-NH—R⁵,—(C₁-C₈-alkenylene)-R⁵, —(C₁-C₈-alkynyl), —(C₁-C₄-alkylene)-S(O)_(r)—R⁵,—(C₁-C₄-alkylene)-O—R⁵, or —(C₁-C₄-alkylene)-NH—R⁵; R⁵ is —COO—R⁶,—(C═O)—R⁶, —(C₁-C₇)-cycloalkyl, phenyl, naphthyl, thienyl, thiophenyl,furanyl, pyridyl, pyrimidyl, dihydropyrimidine-2,4-dion-6-yl, chromanyl,phthalimidoyl, or thiazolyl, wherein the rings are unsubstituted, or aresubstituted up to twice by F, Cl, Br, —OH, —CF₃, —NO₂, —CN, —OCF₃,—(C₁-C₆)-alkyl, —O—(C₁-C₆)-alkyl, —COOH, —COO(C₁-C₆)alkyl, —CONH₂,—CONH(C₁-C₆)alkyl, —CON[(C₁-C₆)alkyl]₂, —CONH(C₃-C₆)cycloalkyl, —NH₂,—NH—CO—(C₁-C₆)-alkyl, —NH—CO-phenyl, or pyridyl; R⁶ is H, or—(C₁-C₆)alkyl; l, m, n are 0; o is 1; p is 0 or 1; q is 0 or 1; and r is0, 1, or
 2. 4. A pharmaceutical composition, comprising at least onecompound or salt thereof as claimed in claim 1 and a pharmacologicallytolerated excipient.